NIAID conducts and supports research to prevent, diagnose, and treat infectious and immunological diseases that affect the health of women and girls.
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Composition of Female Genital Tract Microbiome May Affect Risk of HIV Infection
HIV prevalence in young African women is up to eight-fold higher than in young African men, suggesting that biological factors in the female genital tract (FGT) may increase susceptibility to infection. It has previously been hypothesized that certain types of bacteria that naturally colonize the FGT may be linked to decreased rates of HIV infection.
To test this hypothesis, NIAID-funded researchers turned to Females Rising through Education, Support and Health (FRESH), an ongoing trial funded by the Bill & Melinda Gates Foundation. This trial comprises healthy, HIV-uninfected, 18- to 23-year-old black South African women who are provided with intensive HIV prevention counseling and HIV testing. Using genomic sequencing, the scientists studied the assemblage of bacteria and viruses that comprise the reproductive tract microbiota of participants in the FRESH study, and identified four distinct types of FGT bacterial community structures, or cervicotypes. The most prevalent cervicotypes included a diverse collection of bacteria and low levels of Lactobacillus bacteria, a group of bacteria thought to promote vaginal health.
Despite HIV prevention counseling and frequent HIV testing, 31 of 236 women in the study group became infected with HIV during the study. The researchers found that those women who had high-diversity bacterial communities with low Lactobacillus abundance had a four-fold increase in HIV incidence compared with those who had a cervicotype that was dominated by one type of bacterium, Lactobacillus crispatus. High-diversity cervicotypes that included multiple strains of anaerobic bacteria (bacteria that can live without oxygen) also had elevated levels of inflammation-causing proteins that are associated with increased HIV incidence. The presence of Lactobacillus was associated with decreased levels of inflammation and secreted factors that promote inflammation. By contrast, viral community structures did not vary between HIV-infected and uninfected study participants.
In experiments with mice, the researchers showed that the presence of anaerobic bacteria in the FGT increased the numbers of a type of white blood cell in the female reproductive tract that is targeted by HIV, which could increase the risk of HIV infection. Together, the study findings indicate that distinct bacterial types and communities are associated with an increased risk of HIV infection. The results suggest that South African women may be at increased risk of HIV infection based on their reproductive tract microbiota and emphasize the importance of considering the microbiome when developing new approaches to reduce HIV infection.
Reference: Gosmann C et al., Lactobacillus-Deficient Cervicovaginal Bacterial Communities Are Associated with Increased HIV Acquisition in Young South African Women, Immunity. 2017 Jan 17; 46: 29–37.
High Doses of Anti-HIV Drug Tenofovir Inhibit Wound Healing in Cells of Female Reproductive Tract
Low effectiveness of pre-exposure prophylaxis (PrEP) approaches in women, such as intravaginal application of the anti-HIV drug tenofovir, is partially attributed to lack of adherence to the treatment regimen, but other biological or physiological factors may also play a role. For example, the integrity of physical barriers such as the mucous membranes lining the female genital tract plays a significant role in HIV prevention, and little is known about the process by which the body repairs these tissues and how anti-HIV drugs may affect this process.
NIAID-supported investigators assessed whether two related antiretroviral drugs used in PrEP, tenofovir disoproxil fumarate (TFV) and tenofovir alafenamide (TAF), affect wound repair of female reproductive tract tissue from the outermost layer (epithelium) and inner layers (stroma) of the mucosal lining. They grew female reproductive tract cells in a single layer on plastic laboratory dishes and “scratched” the cell layer with a plastic-tipped implement to simulate tissue injury.
For 24 hours before injury, the researchers exposed epithelial or stromal cells to levels of TFV or TAF that were similar to drug levels used in clinical trials of intravaginal PrEP. They found that TFV, but not TAF, delayed wound healing and the re-establishment of barrier function. Further study will be required to determine the underlying mechanism(s) by which clinical doses of TFV, but not TAF, interferes with wound healing. The results of this study suggest that researchers may wish to consider effects of antiretroviral drugs on wound healing processes in physical barriers to HIV transmission, including the female reproductive tract mucosal lining, in future PrEP clinical trials.
Source: Rodriguez-Garcia et al. Tenofovir inhibits wound healing of epithelial cells and fibroblasts from the upper and lower female reproductive tract. Sci Rep. 2017 Apr 3;8:45725.
Continuing Anti-HIV Therapy After Pregnancy in Non-Breastfeeding Women Provides Benefits
Previous results of one component of the NIAID-funded, multinational Promoting Maternal and Infant Survival Everywhere (PROMISE) study demonstrated that, for HIV-infected mothers whose immune system is in good health and their uninfected infants, a three-drug ART regimen for the mother or daily ART with the drug nevirapine for the infant are equally effective during breastfeeding and associated with very low breastfeeding transmission of HIV from mother to child. However, the health benefits of continuing ART in women after pregnancy had not been rigorously tested.
To address this question, another component of the PROMISE study, the “HAART Standard,” followed 1,652 HIV-positive non-breastfeeding, postpartum women with relatively high CD4 T-cell counts, which are a marker of immune system health. (CD4 T cells are immune cells that are the primary target of HIV.) The study was designed to assess the risks and benefits of continued ART compared with stopping ART after delivery and restarting when clinically indicated by a drop in CD4 T-cell counts below a certain level, or by other factors. Study participants, who had previously received ART only during pregnancy, were randomly assigned either to continue the participant’s optimal ART drug combination or to stop ART after giving birth.
Both study groups showed similar, low rates of AIDS-defining illnesses (certain serious and life-threatening diseases that occur in HIV-positive people) and serious non-AIDS health events. However, the rate of other, less serious, HIV-related illnesses was cut in half in the women on continuous ART. These findings provide further evidence of the benefits of ART for women with early-stage HIV infection. Levels of HIV in the blood were relatively high in the continuous ART group, emphasizing the need to improve adherence to ART regimens in this population.
Reference: Currier JS et al. Randomized trial of stopping or continuing ART among postpartum women with pre-ART CD4 ≥ 400 cells/mm3. PLoS One. 2017 May 10; 12(5): e0176009.
Risk Factors Identified for Cytomegalovirus Infection of Infants Born to HIV-Infected Women
Cytomegalovirus (CMV)—a common virus that infects people of all ages—is an important yet neglected cause of congenital infection (infection at birth), which may lead to developmental delays and hearing loss. Once CMV is in a person’s body, it stays there for life and can reactivate. People infected with CMV can shed (pass) the virus through bodily fluids such as urine, saliva, or breast milk, but little is known about the relevance of CMV shedding in urine and cervical specimens, especially in the context of persons infected with HIV.
NIAID-funded investigators examined whether pregnant, HIV-positive women shed CMV in their urine and whether that could increase the chances of transmitting CMV to their infant. The researchers evaluated a subset of the mother-infant pairs in the perinatal HIV Prevention Trial Network 040 study. This study enrolled women who were identified as HIV-infected around the time they gave birth, and who therefore had not received antiretroviral therapy (ART) before labor. The study compared the efficacy of three different drug regimens to prevent transmission of HIV to the newborns.
Twenty-four (9.2%) of the 260 women tested had detectable CMV in their urine, and 10 of the 260 infants (3.8%) had congenital CMV infection. Women with CMV in their urine during labor were 30 times more likely to have infants with congenital CMV than those without, and 5 times more likely to transmit HIV to their infants. In addition, women who also had gonorrhea were 6 times more likely to have an infant with congenital CMV. Higher levels of HIV in the mother’s blood (viral load) correlated with higher rates of both HIV and CMV transmission to the infant.
These results suggest that maternal CMV urinary shedding at the time of birth is a significant risk factor for both CMV and HIV transmission to infants born to women who did not receive ART during pregnancy. Proper antiretroviral treatment of the mother decreases HIV viral load and drastically decreases the risk of HIV transmission during pregnancy, labor, and delivery. Further studies are needed to investigate whether controlling HIV infection during pregnancy prevents not only HIV but also CMV transmission to infants.
Reference: Adachi K et al. Cytomegalovirus urinary shedding in HIV-infected pregnant women and congenital cytomegalovirus Infection Clin Infect Dis. 2017 Aug 1; 65(3): 405-13.
Immune Cell Population May Protect Brain from Lupus Inflammation
Systemic lupus erythematosus (SLE), or lupus, is an autoimmune disorder that disproportionately affects women and is thought to be caused by a combination of genetic and environmental factors. Multiple organs, including the brain, are often affected by SLE disease. Neurological and psychiatric effects can include headaches, problems with basic brain functions (such as memory loss), and mood disorders. Little is known about factors that contribute to SLE-derived brain symptoms, but a recent NIAID-funded study provides new insights.
Using two mouse models of SLE, researchers discovered a subset of immune cells, known as brain-infiltrating CD8+ T cells, that migrate into brain tissue but not many other affected organs and may have protective effects in SLE. CD8+ T cells are normally found circulating in the bloodstream and lymphatic system, but when activated, they can migrate into the tissues to sites of inflammation or infection. The researchers found that brain-infiltrating CD8+ T cells displayed a specific set of protein markers that promote T-cell entry and retention in the tissue. Additionally, brain tissue from lupus-prone mice expressed molecules that could pair with markers on brain-infiltrating CD8+ T cells to help attract and retain these cells in the brain. The function of brain-infiltrating CD8+ T cells is not yet known, but these cells appeared to be beneficial to lupus-prone mice. SLE symptoms, including brain swelling, bleeding, and inflammation, were more severe in lupus-prone mice genetically engineered to lack CD8+ T cells. Together, these results suggest that brain-infiltrating CD8+ T cells may be specifically directed to the brain, perhaps to protect against SLE-related tissue damage.
Reference: Morawski PA et al. Non-pathogenic tissue-resident CD8+ T cells uniquely accumulate in the brains of lupus-prone mice. Sci Rep. 2017 Jan 18;7:40838.
Study Provides New Insights Into How an Autoimmune Disease Evolves
After viral or bacterial infection, antibody-producing B cells, one major part of the human immune system, migrate to the lymph nodes and enter specialized regions called germinal centers, where they undergo a process called somatic hypermutation. During somatic hypermutation, B cells rapidly divide and their antibody genes accumulate an exceptionally large number of changes called mutations. B cells with antibody mutations that improve their ability to bind pathogens survive and multiply, whereas those with mutations that weaken binding proliferate less and often die. By this process, B cells fine-tune their antibody arsenal against the pathogen.
However, some mutations introduced into antibody genes may be harmful because, by chance, they result in antibodies, known as autoreactive antibodies, that recognize and damage the body’s own cells and tissues. Under normal circumstances, regulatory checkpoints eliminate or control autoreactive B cells. But in some cases, autoreactive B cells evade these checkpoints, leading to autoimmune diseases such as multiple sclerosis or systemic lupus erythematosus (SLE). Exactly how and why an autoimmune disease develops is not fully understood.
NIAID-funded researchers used a mouse model of SLE to gain insights into how this disease develops. They found that replication of a single autoreactive B cell within a germinal center can override normal regulatory checks. The cells proliferated to produce many cells with similar reactivity (called a clone) and launched an attack on the body. Furthermore, once one autoreactive B-cell clone evaded regulation within a germinal center, it could help the survival and expansion of additional B-cell clones that produced other autoreactive antibodies in a process called epitope spreading.
The researchers also showed that, once established, germinal centers harboring autoreactive B cells with one or only a few autoreactive B-cell clones became self-perpetuating and continued to evolve over time. However, these autoreactive B-cell clones still shared certain requirements of normal germinal center B cells: dependence on a protein called Toll-like receptor 7 (TLR7) and interaction with immune cells called T follicular helper cells. These results suggest that germinal centers are central to the development of the autoimmune response, and that approaches restoring or strengthening B-cell development checkpoints within germinal centers may have potential as treatments for autoimmune diseases.
Reference: Degn SE et al. Clonal evolution of autoreactive germinal centers. Cell. 2017 Aug 24;170(5):913-926.e19.
Brd4 Protein May Be Therapeutic Target for Human Papillomavirus
Cervical cancer is the third most common cancer among women and the second most frequent cause of cancer-related deaths worldwide. Nearly all cases of cervical cancer are caused by human papillomaviruses (HPVs), a group of viruses that infect cells called keratinocytes in the outermost layer of skin.
HPVs cannot replicate on their own and must subvert human genes and proteins to drive virus production in infected cells. Because HPV replication is complex, involving successive phases in different layers of skin, it is difficult to reproduce and study in the laboratory. To circumvent this problem, NIAID researchers manufactured HPV-like particles, called HPV quasiviruses, which contain the HPV genome packaged inside a viral shell similar to true HPVs. The researchers then used these HPV pseudoviruses to study the importance of the human cell protein Brd4 in the early stages of HPV infection.
HPV proteins, particularly one called E2, are known to interact with Brd4 in several stages of the viral life cycle, but the importance of Brd4 early in HPV infection is unknown. The researchers created a model infection system that used human keratinocytes genetically manipulated to reduce Brd4 expression. They infected these cells with HPV quasiviruses and found that loss of Brd4 reduced the production of HPV genes and proteins. The researchers also found that Brd4 and the viral protein E2 did not interact during the initial stages of HPV quasivirus replication, suggesting that Brd4 may regulate HPVs using a different mechanism in early-stage versus late-stage infection. These results indicate that Brd4 is integral early in the HPV life cycle and may be a promising therapeutic target for developing measures against HPV infection.
Reference: McKinney CC, et al. B4d4 Activates Early Viral Transcription upon Human Papillomavirus 18 Infection of Primary Keratinocytes. MBio. 2016 Nov 22;7(6) e01644-16.
Newly Identified Virulence Factor Helps Listeria monocytogenes Bacteria Infect the Placenta
The bacterium Listeria monocytogenes (Lm) causes a wide variety of diseases that range from a mild infection of the digestive tract that causes gastrointestinal distress in healthy people to bacterial meningitis, a life-threatening disease that causes swelling of tissues surrounding the brain and spinal cord, in people who have weakened immune systems. Lm is a significant health threat to pregnant women and their unborn children, as infection with this microbe during pregnancy frequently leads to premature delivery and stillbirth.
Despite the serious health risk that infections pose to both mother and unborn child during pregnancy, little is known about the delicate balance the maternal immune system must maintain, both to ensure that the fetus is not seen as “foreign” and attacked by maternal immune cells and to protect it from pathogens. The unique immune relationship between mother and fetus and the relatively high resistance of the placenta to infection by microbes led NIAID-funded researchers to hypothesize that Lm may produce specific molecules, called virulence factors, that enable it to infect the placenta.
The researchers discovered one Lm gene that produces a newly identified virulence factor, InlP. The virulence factor strongly promoted infection of the placenta by Lm in mouse and guinea pig models of Lm infection, but played only a minor role in Lm infection of other maternal organs that were examined. The results suggest that InlP is a virulence factor that helps Lm overcome the placenta’s function as a natural immune barrier against microbes.
InlP may provide a new tool for further study of microbial interactions with the maternal immune system and placenta and could eventually lead to new interventions for the prevention or treatment of infection-related complications in pregnancy.
Citation: Faralla C et al. InlP, a New Virulence Factor with Strong Placental Tropism. Infect Immun. 2016 Nov 18;84(12):3584-96.
Antibody Protects Against Fetal Abnormalities in Mouse Model of Zika Virus Infection
Recent epidemics of Zika virus infection in South and Central America have caused international concern because infection of pregnant women can cause miscarriage and serious birth defects, including microcephaly (an unusually small head). In rare cases, Zika virus infection in adults may also lead to Guillain-Barré syndrome—an autoimmune disorder that causes temporary or even permanent nerve damage. Developing measures to defend against and treat this rapidly emerging infectious disease is a high priority, as no specific therapies or vaccine for Zika virus currently exist.
To develop possible therapies for Zika virus infection, NIAID-supported researchers isolated 29 distinct antibodies from immune cells of three people who were previously infected with Zika virus. The researchers found one antibody, ZIKV-117, that neutralized all types of Zika virus tested, including African, Asian, and American strains. They then assessed the therapeutic potential of ZIKV-117 in pregnant and non-pregnant mice infected with Zika virus.
Giving a single dose of ZIKV-117 to Zika virus-infected male mice with weakened immune systems up to 5 days after infection protected the mice from death, as compared with mice treated with a control antibody. Treating pregnant mice with ZIKV-117 before infection with Zika virus reduced virus levels in the placenta and in the fetal brain and improved fetal survival and health relative to Zika virus-infected pregnant mice that did not receive the antibody. Additionally, administering ZIKV-117 to pregnant mice immediately after they were infected with Zika virus yielded similar results.
This study suggests that ZIKV-117 treatment can reduce transmission of Zika virus from mother to fetus, treat active Zika virus infection, and improve pregnancy outcomes in Zika-infected mice. The findings could contribute to the development of therapies for people infected with Zika virus and may also inform the design of vaccines that can elicit potent protective antibodies against the virus.
Reference: Sapparapu G et al. Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice. Nature. 2016 Dec 15;540(7633):443-447.
Inflammation Plays Role in Malaria-Related Pregnancy Loss and Premature Delivery
Malaria infection during pregnancy triggers widespread, or systemic, inflammation in the woman’s body and in the placenta and can have serious consequences, including pregnancy loss and premature delivery. However, the role that this malaria-induced inflammatory immune response plays in these complications of infection is unknown. To investigate this question, NIAID scientists and their colleagues collected and analyzed blood samples from 638 malaria-infected and uninfected pregnant women who were seen at a prenatal clinic in Mali. The team collected blood samples at the time women enrolled in the study, at week 30–32 of pregnancy, and at delivery. They also collected and analyzed placental blood samples.
Infection with the malaria parasite Plasmodium falciparum was assessed at each clinic visit. Women with confirmed malaria infection were treated according to current guidelines, and preventive treatment against malaria was given as indicated to women who did not have confirmed infection.
The team measured the blood levels of six different cytokines or chemokines—small proteins that are secreted by immune cells and either stimulate or reduce inflammation. They used a mathematical model to analyze the relationships between cytokine and chemokine levels at different time points during pregnancy and the risk of pregnancy loss, defined as miscarriage, stillbirth, or death of the newborn child; or of premature (preterm) delivery, defined as birth before 37 weeks of pregnancy have been completed.
The researchers found that maternal inflammatory immune responses to malaria infection during pregnancy predicted an increased risk of pregnancy loss and preterm delivery. The results emphasize the role of the maternal immune system in influencing pregnancy outcomes during malaria infection, and suggest that it may be possible to use blood tests to predict the risk of malaria-associated pregnancy complications.
Reference: Fried M et al. Systemic inflammatory response to malaria during pregnancy is associated with pregnancy loss and preterm delivery. Clin Infect Dis. 2017 Oct 30;65(10):1729-1735.
New Mouse Model Will Help Researchers Track Zika Virus Transmission
During the 2015–2016 Zika virus epidemic in the Americas, researchers determined that infection of pregnant women with the virus can cause miscarriages and serious birth defects, including microcephaly (an unusually small head), when the virus is transmitted from a pregnant woman to her fetus. To better understand how Zika virus spreads, NIAID scientists developed a mouse model to study sexual transmission of the virus from males to females, as well as transmission from mother to fetus, known as vertical transmission.
Developing the model was challenging because mice have a stronger interferon response and thus naturally defend against Zika virus better than people do. Interferon is a powerful antiviral protein that inhibits the virus. The researchers suppressed the interferon response in specialized laboratory mice that also lack the ability to produce immune cells called T cells and B cells. These mice, called anti-interferon Rag (AIR) mice, have prolonged virus infection in the testes, akin to Zika-infected men. This attribute allowed the investigators to study sexual transmission from male to female mice, which occurred frequently.
In addition to sexual transmission, the research team also showed that Zika virus was transmitted vertically from pregnant AIR mice to their fetuses. Although the Zika virus was found on the maternal side of placental tissue in all infected pregnant mice, only some mouse fetuses and/or pups were infected with the virus, suggesting that the placenta may be a critical barrier in preventing the virus from reaching the fetus. Zika virus infection was more prevalent in born pups than in developing fetuses, suggesting that vertical transmission can occur in both early and late stages of pregnancy. The team also detected the virus in fetal tissues other than mouse brain tissue, such as the lymph nodes.
These results indicate that AIR mice will serve as a valuable model to further explore the details of how Zika virus is transmitted both sexually and vertically, as well as how infection leads to various birth defects, and to investigate potential treatments to block virus transmission.
Reference: Winkler CW et al., Sexual and Vertical Transmission of Zika Virus in anti-interferon receptor-treated Rag1-deficient mice. Sci Rep. 2017 Aug 3; 7(1): 7176.
Studying Chlamydia Infection in Mice May Yield Insights on Infection in Women
Chlamydia is a common sexually transmitted disease (STD) caused by infection with Chlamydia trachomatis (C. trachomatis) bacteria. Chlamydia can have serious consequences in women, including chronic pelvic pain, ectopic pregnancy (pregnancy outside the uterus), and infertility.
Researchers commonly use a mouse model to study chlamydia infection of the female urogenital tract and to research potential treatments and vaccines. However, this model exhibits different characteristics depending on which strain of chlamydia is used—C. trachomatis or the related mouse strain Chlamydia muridarum (C. muridarum)—due to differences in factors such as replication, immune response, and protective immunity.
NIAID researchers examined C. trachomatis and C. muridarum infections in mice following surgical removal of their uterus (hysterectomized mice). The researchers used this mouse model to better understand the effects of these two strains of chlamydia on the surface layer, or epithelial layer, of vaginal tissue independent of adjacent tissues of the upper genital tract (uterus).
By comparing infection by these two chlamydia strains in hysterectomized mice, the researchers determined that C. muridarum bacteria can infect vaginal epithelial tissue in much higher numbers than C. trachomatis and cause a more robust activation of immune cells known as B cells and T cells. This immune activation resulted in higher levels of anti-chlamydia antibodies and other disease-fighting factors known as cytokines, along with better protective immunity.
These results suggest that, in mice, vaginal epithelial tissue is a target for C. muridarum but not C. trachomatis, and may explain why C. muridarum causes a more aggressive disease in mice. Importantly, these results translate to knowledge about C. trachomatis infection in humans, as C. trachomatis does not readily infect vaginal epithelial cells in humans and usually does not induce protective immunity. Also, by studying the differences between these strains, researchers may be able to identify the characteristics that increase disease severity. As such, the results of this study may help researchers better understand the chlamydia infection process and subsequent outcomes in women and thereby aid the development of treatments and vaccines.
Reference: Yang C et al., Infection of Hysterectomized Mice with Chlamydia muridarum and Chlamydia trachomatis. Infect Immun. 2017 Jun 20; 85(7):e00197-17.